Bone Marrow Transplantation (2006) 38, 527–537 & 2006 Nature Publishing Group All rights reserved 0268-3369/06 $30.00 www.nature.com/bmt MEETING REPORT The Second International Meeting on Allogeneic Transplantation in Solid Tumors M Bregni1, NT Ueno2 and R Childs3 1Oncology-Hematology-Bone Marrow Transplant Unit, Department of Oncology, Istituto Scientifico San Raffaele, San Raffaele Hospital, Milan, Italy; 2Department of Blood and Marrow Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA and 3NHLBI, National Institutes of Health, Bethesda, MD, USA In October 2005,the second international meeting on convened in Stresa (Italy) by Marco Bregni, Naoto Ueno, allogeneic transplantation in solid tumors was convened in and Richard Childs under the auspices of the European Stresa (Italy). The aim of this second meeting was to Group for Blood and Marrow Transplantation (EBMT) share clinical experiences of allografting in solid tumors, Solid Tumor Working Party. The first meeting took to discuss preclinical data on the mechanisms of graft- place in Milano, Italy, in June 2002, and was a chance versus-tumor (GVT) effect,and to review methods for for people involved to communicate and discuss initial more efficacious transplant approaches. On the first day, clinical and biological studies of reduced-intensity allo- the most recent results in cancer immunotherapy were grafting in solid tumors.1 The aim of this second meeting reviewed; head-to head comparisons of clinical results was to share experiences of allografting for solid tumors, achieved by standard therapy and by allografting in renal, update data accumulated in this field over the past 3 years, breast,and ovarian cancer were presented. On the second and to discuss methods to develop more efficacious day,GVT mechanisms and preclinical models were transplant approaches. In the meeting introduction, examined; anecdotal reports of a GVT effect in sarcoma, Richard Childs reported that there were approximately pancreatic cancer,prostate cancer,colorectal cancer and 100 attendees from more than 10 different countries present lung cancer were presented; new strategies for optimizing at the meeting. At the last meeting in 2002, there were only transplant outcome were discussed,including patient a handful of case reports and a few small case series of selection,tumor debulking,auto–allo approaches,selec- allotransplants for solid tumors. Since then, there has been tive T-cell depletion,targeting with monoclonal antibo- a steady increase in the number of publications describing dies,use of killer cell immunoglobulin-like receptor-ligand clinical outcome in patients with select solid tumors mismatched natural killer cells. In conclusion,allografting undergoing mostly reduced intensity transplantation, in- in solid tumors is feasible with limited toxicities and cluding: (i) 12 case series describing graft-versus-tumor transplant-related mortality; a GVT effect has been (GVT) effects in renal cell carcinoma (RCC); (ii) four small documented in many different solid tumors; targeting of series reporting breast cancer regression as a consequence the immune response to the tumor by new strategies and of a GVT effect, including a report in this year’s Lancet identification of the target antigen(s) of the GVT effect describing long-term disease-free survival (DFS) in breast are promising areas of research. cancer patients following a tandem autologous followed Bone Marrow Transplantation (2006) 38, 527–537. by allogeneic transplant approach;2 (iii) Numerous case doi:10.1038/sj.bmt.1705479; published online 4 September reports and a few case series reporting evidence for GVT 2006 effects in other solid tumors including metastatic pancreatic Keywords: solid tumors; non-myeloablative allografts; carcinoma, colon carcinoma, ovarian carcinoma and other renal cell cancer; breast cancer; ovarian cancer; immuno- tumors. Importantly, indirect evidence suggests disease therapy regression occurring after allogeneic hematopoietic cell transplantation (HCT) could potentially prolong survival, as a number of series have reported superior survival in patients having GVT effects compared to nonresponders. In October 2005, the second international meeting on A better understanding of the target antigens and allogeneic transplantation in solid tumors (ATST) was immune mechanisms through which GVT effects occur could make transplant outcome more predictable allowing for enrollment of patients who are most likely to respond. Correspondence: Dr M Bregni, Oncology-Hematology-Bone Marrow For the first time, we are now gaining insights into the Transplant Unit, Department of Oncology, Istituto Scientifico San mechanisms through which GVT effects occur. In this Raffaele, San Raffaele Hospital, Milan I-20132, Italy. E-mail: [email protected] meeting, evidence will be presented supporting GVT effects Received 6 April 2006; accepted 1 July 2006; published online 4 being mediated by donor T cells targeting minor histo- September 2006 compatibility antigens expressed broadly on recipient Allografting in solid tumors M Bregni et al 528 tissues and malignant cells as well as antigens that appear in this model, sublethal irradiation acts via indirect to have expression restricted to the tumor. mechanisms rather than direct tumor killing. Lympho- Despite these advances, there currently exist a number of depletion does not result in increased number of transferred obstacles that have impeded progress in this field, including CD8 þ T cells, but it augments their effector function. restrictions by third party payers to fund these clinical Endogenous CD4 þ T cells (but not CD8 þ )suppressthe trials, particularly in the US, and difficulties in obtaining antitumor activity of transferred CD8 þ T cells, and this referrals of patients who are appropriate candidates for the activity can be ascribed to CD4 þ /CD25 þ regulatory T procedure. Of note, the failure of autologous transplant- cells.6 They suppress pmel-1 CD8 þ T cells in vivo. Sublethal ation to prolong survival in women with breast cancer irradiation as well as removal of NK cells enhances the appears to have had a particularly deleterious impact on antitumor efficacy of transferred CD8 þ T cells even referral of patients with solid tumors for investigational in the genetic absence of Tregs. Levels of interleukin allogeneic transplant trials. Remarkably, many practicing (IL)-15 correlated inversely with NK and activated CD8 þ oncologist that are in a position to refer appropriate cell populations, and together with IL-7 enhances the candidates for these types of clinical trials still do not antitumor activity of transferred CD8 þ T cells. Both comprehend the immunotherapeutic nature of this strategy. IL-7 and IL-15 appear to be necessary for the proliferative Also, advances in targeted drug therapy for RCC and other response of transferred CD8 þ T cells; also lipopolysac- solid tumors have recently decreased accrual of patients on charide, which translocates into bloodstream after damage transplant clinical trials. The dramatic reduction in of mucosal barriers by total body irradiation (TBI), transplant procedures for chronic myelogenous leukemia augments the antitumor activity of transferred CD8 þ T that occurred following the success of imatinib therapy cells (Paulos CM, MS in preparation). From these data seems likewise to be occurring for RCC corresponding to and from clinical experience,4 one can assume that a the success and now recent FDA approval of the tyrosine rapid hematological recovery after lymphodepleting kinase inhibitors sorafenib and sunitinib. Furthermore, therapy may be harmful to antitumor response, because of although complete responses do occasionally occur, the competition for cytokines, presence of Tregs and other vast majority of metastatic tumor patients who have had a inhibitory elements. This suggests that a myeloablative, GVT effect have only achieved a PR, with most partial rather than a lymphodepleting therapy, may improve responders ultimately developing progressive disease. adoptive cell transfer-based immunotherapy (Wrzesinski Despite these limitations, allogeneic transplantation brings et al., MS in preparation). Moreover, hematopoietic stem to the table something that most drugs cannot yet offer, cells reinfused after myeloablative therapy produce, or namely the potential to cure. This meeting will bring us up induce the production, of cytokines, growth factors and to date on important observations gleaned from pilot antiapoptotic factors. This strategy will soon be tested in the transplant trials conducted over the past 5 years. One of the clinic. themes of this meeting will be to develop new transplant Maria Grazia Roncarolo (HSR, Milano, Italy) discussed strategies that will allow investigators to move from proof the role of regulatory T cells in inducing tolerance after of principle to more effective allogeneic immunotherapy allogeneic transplantation. She focused her presentation on regimens for metastatic solid tumors. Better markers of the characteristics of different Tregs, and on the clinical disease prognosis and treatment response are needed in exploitation of these T-cell subsets for mediating peripheral order to prognosticate those patients who are mostly likely tolerance to the host and to support immune reconstitu- to benefit from an allogeneic HCT. It is hoped that the tion after allografting. Human naturally occurring discussions of in vitro and preclinical data presented in this CD4 þ CD25 þ T cells